The role of microglial- and neuron-specific MyD88 signaling in tauopathies

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DESCRIPTION (provided by applicant): Prominent filamentous inclusions of microtubule-associated protein tau (MAPT) and neurodegeneration are hallmarks of many neurodegenerative tauopathies. Although the exact etiology of many of these tauopathies remains elusive, neuropathologically they are characterized by intracellular aggregates of hyperphosphorylated MAPT, neuroinflammation and cell death. Increasing evidence suggests that neuroinflammation may directly contribute to the pathophysiology of neurodegenerative tauopathies. However, these studies are largely correlative, and do not provide direct evidence of the role of neuroinflammation in the neurodegenerative disease process. We have recently provided compelling evidence that neuroinflammation, cell-autonomous to microglia, accelerates MAPT phosphorylation, aggregation and behavioral impairment in a mouse model of tauopathy (hTau). Notably, the effects of microglial activation on MAPT pathology were enhanced when mice were deficient for the microglial-specific fractalkine receptor, CX3CR1. We also demonstrated that interleukin-1 (IL1) released by reactive microglia induces MAPT phosphorylation in primary neurons via activating neuronal IL1 receptor (IL1R) and p38 mitogen activated protein kinase (p38 MAPK) pathway. Taken together, these results suggest that inhibition of neuronal IL1R/p38 MAPK may represent a unique potential drug target for human tauopathies. Numerous studies have established that Myeloid Differentiation primary response gene 88 (MyD88) is a key downstream adapter protein for IL1Rs as well as upstream for p38 MAPK activation. Recent studies have suggested that genetic deficiency of MyD88 is protective against hypoxia induced brain injury and mouse model of systemic inflammation. However, the role of MyD88 in mediating IL1 induced MAPT pathology is unclear. Also not clear is whether or not microglial-derived IL1 feeds-back to microglia themselves to induce self-propagating IL1 signaling that contributes to neuronal MAPT pathology and neurodegeneration. Based on our recent study that microglia-specific neuroinflammation is sufficient to induce neuronal MAPT pathology and cognitive impairment via IL1-p38MAPK pathway, the goal of the current proposal is to specifically target microglia-specific and neuronal-specific IL1R signaling via targeted, cel-specific deletion of MyD88 and study its effect on p38 MAPK activation, MAPT pathology, neuroinflammation, neurodegeneration and cognitive function in a mouse model of tauopathy (hTau) under two specific aims. 1) Study the effect of forebrain neuron- restricted deletion of MyD88 in hTau mice on MAPT pathology, neuroinflammation, neurodegeneration and behavioral function at different ages. 2) Study the effect of microglia-restricted deletion of MyD88 in hTau mice on MAPT pathology, neuroinflammation, neurodegeneration and behavioral function at different ages. These studies will provide greater understanding of cell autonomous contribution of IL1R/MyD88 signaling in tauopathies and determine whether MyD88 can serve as a potential therapeutic target against inflammation- mediated MAPT pathology in human tauopathies. PUBLIC HEALTH RELEVANCE: Accumulating evidence suggests that the age-related brain inflammation may play an important role in tau-mediated neurodegeneration in numerous human tauopathies. A recent study from our group has provided compelling evidence that microglia-specific neuroinflammation accelerates tau pathology and cognitive impairment in humanized mouse model of tauopathy (hTau). Notably, interneukin-1 (IL1) released from activated microglia is responsible for upregulating neuronal p38 mitogen activated protein kinase (p38 MAPK) and tau hyperphosphorylation via IL1 receptor (IL1R) signaling pathway. In the current study, the effect of forebrain neuron- and microglia-specific ablation of IL1R signaling via deletion of an IL1R adopter protein, MyD88, on tau pathology, neurodegeneration and behavioral function will be studied in the hTau mouse model of human tauopathy. The outcome of this study will explore the role of neuron-specific as well as feed-forward microglial IL1 signaling in tauopathies and provide mechanistic insights on IL1R/MyD88 signaling at multiple cellular levels as a therapeutic target against human tauopathies.